Global Alert and Response (GAR)

Hepatitis B


Surveillance and control


- Endemicity
- Incidence / Epidemiology
- Trends
- Costs
- Immune prophylaxis
- Vaccines

Hepatitis B disease surveillance procedures should include

  • monitoring disease incidence

  • determination of sources of infection and modes of transmission by epidemiological investigation

  • detection of outbreaks

  • spread containment

  • identification of contacts of case-patients for postexposure prophylaxis

Hepatitis B disease control measures should include

  • immunization, the most effective and cost-saving means of prevention.

  • education of high risk groups and health care personnel to reduce the risk of contracting the virus and to reduce the chances for transmission to others, as well as to promote acceptance of vaccination schemes.

  • screening of blood and blood products to reduce the chance that the blood supply system may contain pathogens like HBV.

Surveillance systems for hepatitis B across Europe vary in their methods and completeness. In many countries notification of HBV infections is mandatory. However, case definitions vary, laboratory confirmation is not always used, reporting systems differ, and distinctions are not always made between the types of viral hepatitis. In addition, underreporting of HBV infection is commonplace. Surveillance systems need therefore to be strengthened and standardized.

For better standardization of surveillance systems, countries should follow the case definition of viral hepatitis B recommended by WHO:

  • A clinical case of acute viral hepatitis is an acute illness that includes the discrete onset of symptoms and jaundice or elevated serum aminotransferase levels (>2.5 times the upper limit of normal)

  • A confirmed case of hepatitis B is a suspected case that is laboratory confirmed: HBsAg positive or anti-HBc-IgM positive, and anti-HAV-IgM negative.

The serological quality of the test used is crucial for firm diagnosis of infection. Countries without ready access to these tests may choose methods to detect HBsAg such as reverse passive haemagglutination (RPHA) or latex bead technology that are inexpensive. While not quite as sensitive as radioimmunoassay (RIA) antigen tests or enzyme-linked immunoabsorbent assay (ELISA), these tests are far better than not testing at all.15   

Regardless of the availability of serological tests, all countries are advised to report all cases of jaundice and suspected viral hepatitis. Countries with laboratory facilities can differentiate further between hepatitis A, B, C, and other types of hepatitis. Surveillance reports should be submitted on a regular basis.

Endemicity
There are no seasonal preferences for primary HBV infections.15, 30

Hepatitis B is highly endemic in all of Africa, some parts of South America, Alaska, northern Canada and parts of Greenland, eastern Europe, the eastern Mediterranean area, south-east Asia, China, and the Pacific Islands, except Australia, New Zealand and Japan. In most of these areas, 5 to 15% of the popu-lation are chronically infected carriers of HBV, and in some areas may also carry HDV, which may lead to severe liver damage.23, 42

Even in low endemicity countries such as the USA, mortality from HBV was five times that from Haemophilus influenzae b (Hib) and ten times that from measles before routine vaccination of children was introduced.

Click here for: World distribution map

Incidence/Epidemiology
The hepatitis B virus is a ubiquitous virus with a global distribution.15, 38

Hepatitis B is one of the world’s most common and serious infectious diseases. It is estimated that more than one third of the world’s population has been infected with the hepatitis B virus. About 5% of the population are chronic carriers of HBV , and nearly 25% of all carriers develop serious liver diseases such as chronic hepatitis, cirrhosis, and primary hepatocellular carcinoma. HBV infection causes more than one million deaths every year.15, 23, 30, 39

The HBsAg carrier rate varies from 0.1 to 20% in different populations around the world. The incidence of the HBsAg carrier state in populations is related most importantly to the incidence and age of primary infection.23

In low-risk areas of the world, the highest incidence of the disease is seen in teenagers and young adults. Despite the low incidence of disease seen in the general population, certain groups who are sexually promiscuous or who have frequent contact with blood or blood products have a high rate of HBV infection. Nevertheless, the availability of an effective vaccine, optimized blood donor screening, and better sterilization procedures for blood derivatives have lowered substantially the infection risk.15

In endemic areas of Africa and Asia, the epidemiological patterns differ from those seen in north America and western Europe. In these regions, most infections occur in infants and children as a result of maternal-neonatal transmission or close childhood contact, although percutaneous exposure with contaminated needles or following unsafe injections is always a possibility in these countries.15, 23

The chronic liver disease and HCC associated with HBV infections are among the most important human health problems in high-prevalence regions.

Trends
There is no seasonal trend similar to that observed in hepatitis A infections.15

Epidemics are unusual unless associated with contaminated blood or blood products, or the use of nonsterile injection equipment.

Evaluations of infant vaccination programs need to compare vaccination coverage data with population-based serological analyses, since most HBV infection in young children are asymptomatic and are therefore not detected  in surveillance studies of acute disease. A decline in the prevalence of chronic disease is on the other hand a major indicator of program success and infection reduction.23

A reduction in the prevalence of chronic HBV infection after implementation of infant immunization programmes has been demonstrated in high endemicity areas like Alaska, Taiwan, Indonesia, Polynesia, and the Gambia.23

The implementation of routine infant immunization will eventually achieve broad-population-based immunity to HBV infection and prevent HBV transmission among all age groups. However, it is only in the longer term that infant immunization in countries that have adopted the HBV vaccination programme will affect the incidence of hepatitis B and the severe consequences of chronic infections.37

Costs
Hepatitis B is a significant health problem and vaccination saves both money and lives. Consideration of epidemiological and economic data shows that universal vaccination strategies are cost-effective even in countries with a low prevalence of hepatitis B. Hepatitis B prevention programmes incorporating universal immuni-zation of newborns and/or adolescents have been highly successful in Spain and Italy, and their success offers an exemplary model for other countries.39

Even in low HBV endemicity areas of the world it is more cost-saving for the society to follow prevention programmes against HBV infection for the younger age groups than to face an increase in chronic liver disease among adults.37

The cost of vaccines has fallen dramatically since the early 1980s, to the point that paediatric-dose vaccine in quantities of several hundred thousand can be found for less than US$ 1 per dose in developing countries. However, even at US$ 0.5 per dose, a three-dose series costs more than the other six childhood vaccines recommended by the WHO Expanded Programme on Immunization (EPI) combined (BCG, three doses of DTP, four doses of OPV, and measles vaccines). Cost therefore remains the primary obstacle to worldwide control of hepatitis B.23

In the USA, the price of vaccination per dose is estimated at US$ 41 if given by a general practitioner, US$ 15 if administered through an existing childhood immunization programme, and US$ 17 if given through the school medical system.37

Immune prophylaxis
In 1974, a special lot of high-titred human hepatitis B IG designated HBIG was introduced. HBIG is similar to conventional IG preparations except that it is prepared from plasma preselected for a high titre of anti-HBs (>100 000 IU/ml of anti-HBs by RIA). The process used to prepare HBIG inactivates and eliminates HIV from the final product. There is no evidence that HIV can be transmitted by HBIG.3, 15, 23, 31

HBIG protects by passive immunization if given shortly before or soon after exposure to HBV. The protection is immediate, but it lasts only 3 to 6 months. HBIG is not recommended as pre-exposure prophylaxis because of high cost, limited availability, and short-term effectiveness. HBIG is generally not affordable in developing countries.15, 23, 31

HBIG should be given to adults within 48 h of HBV exposure.23

Maternal-neonatal transmission of HBV and the subsequent development of chronic hepatitis B in infected children has been reduced drastically, when HBIG was given to newborn babies of HBV carrier mothers in conjunction with the first dose of HB vaccine.15, 23

HBV vaccination and one dose of HBIG, administered within 24 h after birth, are 85 to 95% effective in preventing both HBV infection and the chronic carrier state. HB vaccine administered alone beginning within 24 h after birth, is 70-95% effective in preventing perinatal HBV infection.23

Routine infant immunization programmes have shown that the currently available vaccines confer as much protection upon the infants as does a combination of vaccine and HBIG. Therefore, the additional expenses for the administration of HBIG can be avoided.23

With the availability of a vaccine against hepatitis B and mandatory screening of blood donors for HBsAg and anti-HBc, there is little justification for the use of HBIG in preexposure prophylaxis, except for individuals failing to respond to vaccine, or in patients with disorders that preclude a response (e.g. agammaglobulinaemia).15, 23, 31

However, situations exist where postexposure prophylaxis is essential or desirable. The effectiveness appears to diminish rapidly if administration is delayed for more than 3 days. Passive immunization is now generally combined with active immunization induced by vaccine, providing immediate protection and more durable immunity.23

Click here for: Safety of immune globulin
Click here for: Postexposure prophylaxis

Vaccines
Hepatitis B is a vaccine-preventable disease, but although global control of hepatitis B is achievable, it has not been attained yet.5, 36, 37 In fact, a large pool of carriers and the burden of their disease remains, so that efforts must necessarily continue to treat the various stages of disease.

HB vaccine is the first and currently the only vaccine against a major human cancer. Vaccination is the most effective tool in preventing the transmission of HBV and HDV. Vaccines are composed of the surface antigen of HBV (HBsAg), and are produced by two different methods: plasma derived or recombinant DNA. When administered properly, hepatitis B vaccine induces protection in about 95% of recipients.5

A safe and effective vaccine against HBV infection has been available for 20 years. HB vaccine is effective in preventing HBV infections when it is given either before exposure or shortly after exposure, At least 85%-90% of HBV-associated deaths are vaccine-preventable.

Despite the availability of a vaccine, worldwide infection persists.

Systematic hepatitis B vaccination of newborns renders the screening of pregnant women for HBsAg-status before delivery superfluous.23

WHO recommends that hepatitis B vaccine be included in routine immunization services in all countries. The primary objective of hepatitis B immunization is to prevent chronic HBV infections which result in chronic liver disease later in life. By preventing chronic HBV infections, the major reservoir for transmission of new infections is also reduced,

Plasma-derived vaccines 

These vaccines, derived from the plasma of HBsAg-positive donors,  consist of highly purified, formalin-inactivated and/or heat-inactivated, alum-adsorbed, hepatitis B subvirion particles (22 nm) of HBsAg that are free of detectable nucleic acid, and, therefore, noninfectious.15, 23

The first plasma-derived hepatitis B vaccines manufactured in the USA and in France were licensed in 1981-1982 (Heptavax B®, Merck & Co., Hevac B®, Institut Pasteur). They contain 20 μg/ml HBsAg and the preservative thimerosal at a concentration of 1:20 000.3, 15, 31

Plasma-derived HB vaccines are no longer produced in North America or western Europe, but several hundred million doses are produced in the Republic of Korea, China, Vietnam, Myanmar, India, Indonesia, Iran and Mongolia.15, 23, 31

More than 200 million doses of plasma-derived vaccines have been distributed globally, and the safety record is impressive. Local reactions are generally insignificant clinically and are limited to mild pain or discomfort at the injection site in up to 25% of the vaccine recipients.15

Recombinant DNA yeast-derived or mammalian cell-derived vaccines

In the mid-1980s, an alternative genetically engineered vaccine became available. The new technologies offer manufacturers a shorter production cycle (12 instead of 65 weeks), batch-to-batch consistency, and continuous supply of material, allowing the replacing of plasma-derived vaccines available on the market.15, 31

In recombinant DNA technology, the S gene (pre-S1, pre-S2, S) is cloned and isolated, inserted into an expression plasmid and introduced into yeast (S. cerevisiae) or mammalian (Chinese hamster ovary, CHO) cells. The desired protein(s) is(are) expressed and assembled into 22 nm antigenic particles.15, 23, 31

As on natural HBsAg particles, the a epitope that elicits the most important immune response is exposed on the surface of artificial particles. Natural and artificial particles differ in the glycosylation of HBsAg.15, 23

The only mammalian cell-derived vaccine available is GenHevac B® (Pasteur Mérieux Connaught, 1993). GenHevac B® contains both preS2 and S proteins.15

The two major yeast-derived hepatitis B vaccines that are licensed in most countries are Engerix-B® (SmithKline Beecham, 1992) and Recombivax HB® (Merck & Co.). Both recombinant products contain nonglycosylated HBsAg particles (only S protein) that have been physicochemically purified, adsorbed on aluminium hydroxide, and preserved with thimerosal. Only Recombivax HB® is treated with formaldehyde.15

The yeast-derived HB-VAX DNA® (Pasteur Mérieux MSD), containing only the S protein, is produced in France.

Recombinant HB vaccines are produced in Belgium, China, Cuba, France, India, Israel, Japan, the Republic of Korea, Switzerland, the USA and Vietnam.23

India has developed an indigenous yeast-derived, recombinant DNA vaccine, Shanvac-B® (Santha Biotechnics, 1997). At about US$ 14 for three doses, Shanvac-B® is within the reach of the EPI.2

A licence application in both Europe and the USA has been filed in 1998 for Hepagene® (Medeva), the first recombinant hepatitis B vaccine to incorporate significant levels of HBV’s pre-S1 and pre-S2 epitopes, and S protein. Further, like the surface of the virus itself, Hepagene®’s surface proteins are glycosylated. The result is that Hepagene® closely mimics the surface of HBV and produces a better immune response than that of other recombinant HB vaccines. Hepagene® has also been studied as an immunotherapy for the treatment of hepatitis B.29

Cross-protection by different serotype vaccines against different HBV subtypes has been observed in chimpanzees.15 Postexposure immunization after an HBV challenge has also been effective in chimpanzees.15, 28

Vaccination of HBV carriers is safe but ineffective in eliminating HBsAg from chronically infected individuals.15 The HBV vaccine produces neither therapeutic nor adverse effects for individuals who possess antibodies against HBV from a previous infection. Passively acquired antibody will not interfere with active immunization.

Combination vaccines

The HBsAg vaccines (HB) can be combined with other vaccines such as Calmette-Guérin bacillus (BCG), measles, mumps, and rubella (MMR), Haemophilus influenzae b (Hib), and diphtheria, tetanus and pertussis combined with polio (DTP-polio). SmithKline Beecham offers a tetravalent DTP-HB vaccine, and a combined hepatitis A - hepatitis B vaccine.15

The combined hepatitis A and B vaccine (Twinrix®, SmithKline Beecham) has been introduced in Australia, Canada and some countries in Europe in 1997. In its adult formulation it contains 720 EL.U. of hepatitis A antigen (Havrix®) and 20 μg of hepatitis B surface antigen (Engerix®-B) adsorbed onto aluminium salts.15, 34

Neonates born to mothers who are HBeAg-positive should be given a combination of passive and active immunization to provide immediate protection with HBIG in the first 6 h after delivery, followed by long-term immunity with the vaccine. At the currently recommended doses, HBIG does not interfere with the active immune response of the vaccine. When concurrent administration of HBIG and vaccine are contemplated, different sites should be used.15

The vaccines are to be administered by intramuscular injection in the anterolateral aspect of the thigh of newborns and infants or the deltoid (arm) muscle of children and adults in order to achieve optimal protection.3, 15

The recommendation for universal infant vaccination neither precludes vaccinating adults identified to be at high risk of infection nor alters previous recommendations for postexposure prophylaxis for hepatitis B.3  

Vaccine batches should be stored at 2-8°C but not frozen. Freezing destroys the potency of the vaccine since it dissociates the antigen from the adjuvant alum interfering with the immunogenicity of the preparation.15

The vaccine is thermostable and neither reactogenicity nor immunogenicity are altered after heating at 45°C for 1 week or 37°C for 1 month.23  

Factors that may reduce the immunogenicity of hepatitis vaccines include age (>40 years), weight, genetics, haemodialysis, HIV infection, immunosuppression, tobacco smoking, subcutaneous injection, injection into the buttocks, freezing of vaccine, and accelerated schedule.15, 31

An initial anti-HBs titre of >10 IU/l is regarded as being protective. Although the initial anti-HBs titre is followed by a decline of antibody, a rapid anamnestic response develops after exposure to the virus.23, 31   

The duration of vaccine-induced immunity is uncertain but it is definitely long term (>15 years). At present there is no recommendation for the administration of booster doses, although future studies could demonstrate a need for boosters.15, 23, 31 

A recent study designed to determine the safety and immunogenicity of a DNA vaccine consisting of a plasmid encoding hepatitis B surface antigen delivered into human skin suggests that this gene delivery system may induce a booster response, but that the vaccine at the dose used (0.25 ug) did not induce primary immune responses.32

Click here for: Hepatitis B vaccines available internationally
Click here for: Recommendations for preexposure immunization with hepatitis B vaccine
Click here for: Recommended dosages and schedules for preexposure prophylaxis with hepatitis B vaccines licensed in the US
Click here for: Anti-HBs seroconversion rates after hepatitis B vaccination
Click here for: Recommendations for postexposure prophylaxis for perinatal or sexual exposure to HBV
Click here for: Vaccine safety
Click here for: Hepatitis B virus mutants
Click here for: Hepatitis B vaccine immunization policies

 


World distribution map

 

 

From: World Health Organization. Introduction of hepatitis B vaccine into childhood immunization services, Geneva, WHO, 2001 (unpublished document WHO/V&B/01.31; available on request from Department of Vaccines and Biologicals, World Health Organization, 1211 Geneva 27, Switzerland)51

Geographical distribution of chronic hepatitis B virus infection. (Note: The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.)


Safety of immune globulin

In 1972, routine screening of plasma donors for HBsAg was introduced, resulting in a sharp decline in the concentration of HBsAg inadvertently added to donor pools destined for IG production.15

Since 1977, all tested lots of commercial IG contain anti-HBs at a titre of at least 1:100 by RIA.15

Side effects associated with the administration of IG are rare.15


Postexposure prophylaxis

From: Hollinger FB, Liang TJ. Hepatitis B Virus. In: Knipe DM et al., eds. Fields Virology, 4th ed., Philadelphia, Lippincott Williams &Wilkins, 2001:2971-3036,15 with permission (http://lww.com).

Algorithm for postexposure prophylaxis of healthcare personnel exposed to a potentially infectious source of HBV.

Abbreviation: HBIG, high-titred

 specific hepatitis B immune globulin.15


Hepatitis B vaccines* available internationally

Manufacturer

Brand name§

Country

Type

Centro de Ingenieria Genetica Y Biotecnologia

Enivac-HB

Cuba

Recombinant DNA

Chiel Jedang

Hepaccine-B

South Korea

Plasma derived

Korea Green Cross

Hepavax B

South Korea

Plasma derived

Korea Green Cross

Hepavax-Gene

South Korea

Recombinant DNA

LG Chemical

Euvax B

South Korea

Recombinant DNA

Merck Sharp & Dohme

Recompivax H-B-Vax II

United States

Recombinant DNA

Merck Sharp & Dohme

Comvax

United States

Combined Hib and (recombinant)

Pasteur Mérieux Connaught

Genhevac B

France

Recombinant DNA (mammalian cell)

SmithKline Beecham

Engerix-B

Belgium

Recombinant DNA

SmithKline Beecham

Twinrix

Belgium

Combined hepatitis A and B (recombinant)

SmithKline Beecham

Tritanrix-HB

Belgium

Combined DTP and recombinant

SmithKline Beecham

Infanrix-HB

Belgium

Combined DTP (acellular P) and HB (recombinant)

Swiss Serum and Vaccines Institute

Heprecombe

Switzerland

Recombinant DNA (mammalian cell)

* Numerous producers who sell only in country of production are not listed. Presence on this list does not imply endorsement of these products by the World Health Organization.
§ Brand names may vary in different countries.
Abbreviations: DTP, diphteria, tetanus and pertussis; HB, hepatitis B; Hib, Haemophilus influenza type b.

From: Mahoney FJ, Kane M. Hepatitis B vaccine. In: Plotkin SA, Orenstein WA, eds. Vaccines, 3rd ed. Philadelphia, W.B. Saunders Company, 1999:158-182.23 with permission.

 


Recommendations for preexposure immunization with hepatitis B vaccine

Here is a list of groups for whom preexposure vaccination is recommended. If all members of these groups were immunized, the incidence of hepatitis B would decrease rapidly.3, 5, 15

·                     Infants (universal immunization)

·                     Infants and adolescents not vaccinated previously (catch-up vaccination)

·                     Persons with occupational risk (exposure to blood or blood-contaminated environments) and students of health-care professions before they have blood contact

·                     Clients and staff of institutions for the developmentally disabled and susceptible contacts in day-care programs who are at increased risk from HBV carrier clients with aggressive behaviour or special medical problems that increase the risk of exposure

·                     Haemodialysis patients. Vaccination before dialysis treatment is recommended

·                     Recipients of frequent and/or large volumes of blood or blood components

·                     Susceptible injecting drug abusers

·                     Sexually active men or women (homosexual and bisexual men; persons with recently acquired sexually transmitted disease; prostitutes; promiscuous heterosexuals)

·                     Susceptible inmates of long-term correctional facilities who have a history of high risk behaviour

·                     Household contacts and sex partners of HBV carriers

·                     Populations with a high incidence of disease

·                     International travellers to areas of high HBV endemicity if specific at-risk circumstances exist.50

·                     Transplant candidates before transplantation

In 1991 the WHO/EPI recommended that HB vaccine be included in national  immunization programmes in all countries with an HBV carrier rate of 8% or over by 1995, and in all other countries (regardless of HBsAg prevalence) by 1997. Countries with a low prevalence may consider immunization of all adolescents (before age of 13) as an addition or alternative to infant immunization.

So far (March 2002) 151 countries (Albania, American Samoa, Andorra, Anguilla, Antigua and Barbuda, Argentina, Armenia, Australia, Austria, Azerbaijan, Bahamas, Bahrain, Barbados, Belarus, Belgium, Belize, Bermuda, Bhutan, Bolivia, Bosnia and Herzegovina, Botswana, Brazil, British Virgin Islands, Brunei Darussalam, Bulgaria, Cambodia, Canada, Cayman Islands, China, C.N. Mariana Islands, Colombia, Cook Islands, Costa Rica, Côte d'Ivoire, Cuba, Cyprus, D. People's R. of Korea, Dominica, Dominican Republic, Ecuador, Egypt, El Salvador, Eritrea, Estonia, Fiji, France, French Guiana, French Polynesia, Gambia, Georgia, Germany, Ghana, Greece, Grenada, Guadeloupe, Guam, Guyana, Honduras, Indonesia, Iran (Islamic Republic of), Iraq, Israel, Italy, Jamaica, Jordan, Kazakhstan, Kenya, Kiribati, Kuwait, Kyrgyzstan, Lao People's D. R., Latvia, Lebanon, Libyan Arab Jamahiriya, Lithuania, Luxembourg, Madagascar, Malawi, Malaysia, Maldives, Marshall Islands, Martinique, Mauritius, Mexico, Micronesia (Federated States of), Monaco, Mongolia, Montserrat, Morocco, Mozambique, Nauru, Netherlands Antilles, New Caledonia, New Zealand, Nicaragua, Niue, Oman, Pakistan, Palau, Panama, Papua New Guinea, Paraguay, Peru, Philippines, Poland, Portugal, Puerto Rico, Qatar, Republic of Korea, Romania, Rwanda, Saint Kitts and Nevis, Saint Vincent and the Grenadines, Samoa, San Marino, Saudi Arabia, Seychelles, Singapore, Slovakia, Slovenia, Solomon Islands, South Africa, Spain, Suriname, Swaziland, Syrian Arab Republic, Tajikistan, Thailand, The Republic of Moldova, Tokelau, Tonga, Trinidad and Tobago, Tunisia, Turkey, Turkmenistan, Turks and Caicos Islands, Tuvalu, Ukraine, United Arab Emirates, United Nations Relief and Works, United Republic of Tanzania, United States of America, Uruguay, U.S. Virgin Islands, Uzbekistan, Vanuatu, Venezuela, Viet Nam, Wallis and Futuna Islands, West Bank and Gaza, Yemen, Zimbabwe (from: WHO/V&B/VAM)) have introduced hepatitis B vaccine within their national immunization programmes.19, 37, 42

In other countries, universal vaccination is still being postponed. The reasons for this are the weakness of a social commitment to preventive medicine and vaccines, the lack of medical and public awareness, the view of hepatitis B infection as a limited public health problem that does not justify the expense and other efforts of universal immunization, and the financial burden of national programmes.17, 37, 42

Vaccine coverage in rural areas of many HBV high endemicity countries is a logistical and economic challenge. Since 1994 UNICEF, WHO, and several other international donor agencies have been helping developing countries to obtain HB vaccine and implement national programmes.


Recommended dosages and schedules for preexposure prophylaxis with hepatitis B vaccines licensed in the USA

Currently, two primary immunization doses given intramuscularly are followed using three injections at 0, 1, and 6 months or four injections at 0, 1, 2, and 12 months.3, 15, 31 For routine preexposure prophylaxis, the three-injections schedule is preferred, whereas the four-dose regimen is preferred for immunocompromised patients or in postexposure prophylaxis situations.

Group

Heptavax-HB®

(0, 1, 6 months)

Recombivax HB®

(0, 1, 6 months)

Engerix B®

(0, 1, 6 months°)

Infants of HBsAg-positive mothers

10 μg

5.0 μg

(US$ 28.84)*

10 μg

Children (≤10 years)

10 μg

5.0 μg

(US$ 28.84)*

10 μg

Adolescents (11-19 years)

20 μg

5.0 μg

(US$ 28.84)*

20 μg

(US$ 54.35)*

Adults (≥20 years)

20 μg

10 μg

(US$ 59.50)*

20 μg

(US$ 54.35)*

Immunocompromised patients

40 μg

40 μg

(US$ 167.91)*

40 μg

° Alternate 4-dose schedule of 0, 1, 2, and 12 months is standard for immunocompromised patients and when more rapid induction of antibody is desired.
* Prices are the average wholesale costs per single-unit dose in the
USA.

HB vaccines are packaged to contain 10-40 μg of HBsAg protein/ml after adsorption to aluminium hydroxide (0.5 mg/ml), thimerosal (1:20000 concentration) is added as a preservative.3, 49

A four-dose schedule with a yeast-derived vaccine (2.5 μg of HBsAg  at 0, 1, 2, and 12 months) provides a protective efficacy rate that is comparable with that found after combined HBIG plus vaccine therapy.

Vaccinees examined for anti-HBs concentration after completion of the basic immunization doses may show an inadequate level of protection if their anti-HBs values are below 10 mIU/ml. In these cases, booster doses consisting of one or two additional injections of vaccine are recommended.7, 12, 15

The course of vaccination should never be started over when a scheduled dose is missed or postponed, but should be completed in due course.

The immune response when one or two doses of a vaccine produced by one manufacturer are followed by subsequent doses from a different manufacturer is comparable with that resulting from a full course of vaccination with a single vaccine.3     

There is no evidence that nonresponders to plasma-derived vaccine will respond to genetically engineered vaccines.

Neither HBIG nor normal IG is recommended for preexposure prophylaxis because active immunization with HBsAg (vaccination) is more effective and gives long-term protection.15


Anti-HBs seroconversion rates after hepatitis B vaccination (%)

Neonates

>95%

Age (years)

 

  2-19

~99%

  20-29

~95%

  30-39

~90%

  40-49

~85%

  50-59

~70%

  >59

~50%

Renal failure, HIV infection, other immunosuppression

50-70%

Liver disease

60-70%

Abbreviation: HIV, human immunodeficiency virus.

From: Robinson WS. Hepatitis B virus and hepatitis D virus. In: Mandell GL, Bennett JE, and Dolin R, eds. Principles and Practice of Infectious Diseases, 4th ed. New York, Churchill Livingstone, 1995:1406-1439,31 with permission.


Recommendations for postexposure prophylaxis for perinatal or sexual exposure to HBV

 

HBIG

Vaccine

Exposure

dose (i.m.)

timing

dose (i.m.)°

timing (first dose)

perinatal

0.5 ml

<12 h of birth

0.5 ml

<12 h of birth

sexual

0.06 ml/kg

<14 days since last exposure

1.0 ml

Concurrent with HBIG (first dose)

° Each ml contains 10 μg Recombivax HB® or 20 μg Engerix-B®; subsequent doses at 1 and 6 months for either vaccine or the alternate four-dose schedule (0, 1, 2, and 12 months) for Engerix-B®. HBIG and vaccine should be administered at different sites.

Abbreviations: ACIP, Advisory Committee on Immunization Practices;

From: Centers for Disease Control and Prevention. Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination: recommendations of the immunization practices advisory committee (ACIP). Morbidity and Mortality Weekly Report, 1991, 40:1-19.3

All pregnant women should be routinely tested for HBsAg before delivery, so that newborns of positive mothers can be appropriately immunized after birth. In developing countries, where funds and infrastructure to screen pregnant women may not be available, routine vaccination of infants at birth may be appropriate.3

Postexposure immunization should especially be considered for neonates born of HBsAg-positive mothers. Such infants are infected commonly, especially when mothers are HBeAg-positive, and the risk of becoming chronic carriers is extremely high (90%). When HBIG is given within the first hours after birth, the risk of infection can be reduced to 20%.3, 15, 31

Ongoing clinical trials will determine whether HBIG alone, HBIG and vaccine, or vaccine alone is sufficient to prevent hepatitis B after percutaneous inoculation, oral ingestion, or direct mucous membrane contact with HBsAg-positive materials.15

No postexposure prophylaxis is indicated for contamination of unbroken skin, for staff members who provide routine care of patients with hepatitis B, or for people who inadvertently share food or utensils with a person who subsequently develops hepatitis B unless there are extenuating circumstances.15

Following sexual exposure to an infected person, it is currently recommended to use both HBIG and hepatitis B vaccine.15, 31

For no reason should an HBIG be delayed until the results of HBV tests become available. There is no precedent for recommending HBIG prophylaxis if HBV exposure has occured more than 7 days earlier. If a significant delay is anticipated in obtaining or dispensing the HBIG, conventional IG containing anti-HBs should be substituted for the HBIG until HBIG can be dispensed.15, 31


Vaccine safety

Side effects are local, of low intensity and short duration, involving a generally clinically insignificant soreness at the injection site or a mild to moderate fever for 1-2 days following injection.5, 15, 23, 31

Persons allergic to vaccine components should follow the recommendations for the use of HBIG.31

Neither pregnancy nor lactation should be considered a contraindication to vaccination of women.3, 23

Vaccination does no harm to HBV-immune or HBV-carrier recipients.

Hypersensitivity reactions can be expected in some individuals who are allergic to yeast antigens. The yeast-derived vaccine is not recommended for such individuals.23, 31

Both plasma-derived and yeast-derived hepatitis B vaccines are effective and safe for the prevention of HBV infection.15, 31

A potential problem for hepatitis B vaccines may be the naturally occurring mutants that alter HBsAg specificity and permit mutant virus to escape the immune response to vaccination.29 Such mutants are rare, but if they were to arise more frequently, they would require changes in HBV vaccines and in diagnostic testing procedures.31 As of today no such effect with public health implications has been observed (see section on “Hepatitis B virus mutants”).

There is no scientific evidence that hepatitis B vaccine causes or exacerbates multiple sclerosis (MS) or other central nervous system demyelinating diseases.5, 23, 25, 31, 40, 46-48 

While any risk of MS following hepatitis B vaccination is hypothetical and so far unconfirmed, the risk of HBV infection and disease in non-immunized individuals is real. Hepatitis B causes about 4 million acute infections worldwide per year, and currently there are more than 350 million HBV carriers, about 25% of whom will die from cirrhosis or primary liver cancer.39, 40

Hepatitis B vaccines are safe, more than 90% effective in preventing HBV infection, and particularly cost-effective. Unfortunately, unsubstantiated claims that HB vaccines might cause MS are reducing the uptake of this important vaccine in a few countries.5

WHO strongly recommends that all countries already using hepatitis B vaccine as a routine vaccine in their national immunization programmes continue to do so, and that all countries not yet using the vaccine begin as soon as possible.


Hepatitis B virus mutants

Antibodies to the antigenic determinant a mediate cross-protection against all subtypes.52

The epitope a is located in the region of amino acids 124-148 of the major surface protein, and appears to have a double-loop conformation.52

During a study on the immunogenicity and efficacy of hepatitis B vaccines in Italy, some patients who had mounted a successful immune response to the vaccine and become anti-HBs positive, later became infected with HBV. A characteristic for these cases was the coexistence of non-complexed anti-HBs and HBsAg, in the presence of other markers of HBV infection. Analysis of HBsAg using monoclonal antibodies suggested that the a epitope was either absent or masked. Sequencing of the HBV DNA isolated from these patients revealed a mutation in the sequence encoding the a epitope, showing a substitution of arginine for glycine at amino acid position 145 (G to A substitution, nt 587). This point mutation in the HBV genome has been found subsequently in viral isolates from Singapore, Japan, US, Germany, UK, Brunei and elsewhere.52, 53

The region in which the mutation occurs is an important epitope to which vaccine-induced neutralizing antibodies bind, but the mutant virus is not neutralized by antibody to this specificity. The mutant virus replicates efficiently, implying that the amino acid substitution does not alter the binding of virions to the liver cell.52, 53

Variants of HBV with altered antigenicity of the envelope protein show that HBV is not as antigenically singular as thought previously.52, 53

Two concerns arise from this finding: failure to detect HBsAg may lead to transmission through donated blood or organs, and mutant HBV may infect individuals who are anti-HBs positive after immunization.

Mutant strains of HBV are being sought and studied in many laboratories.28, 44, 52, 53


Hepatitis B vaccine immunization policies

From: WHO/V&B/VAM

Progression of countries using hepatitis B vaccine in their national immunization system. (Note: The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.)

Share